BACKGROUND We investigated the potential associations between cerebro-spinal fluid (CSF) levels of phosphorylated tau (P-tau) and total tau (T-tau) with short-term response to cholinesterase inhibitor (ChEI) treatment, longitudinal outcome and progression rates in Alzheimer's disease (AD). METHODS This prospective, observational study included 129 participants clinically diagnosed with mild-to-moderate AD, who underwent a lumbar puncture. The CSF biomarkers amyloid-β1-42 (Aβ42), P-tau and T-tau were analysed with xMAP technology. Cognitive, global, instrumental and basic activities of daily living (ADL) capacities at the start of ChEI therapy and semi-annually over 3 years were evaluated. RESULTS All patients had abnormal Aβ42 (A+). Fifty-eight individuals (45%) exhibited normal P-tau and T-tau (A+ T- (N)-), 12 (9%) abnormal P-tau/normal T-tau (A+ T+ (N)-), 17 (13%) normal P-tau/abnormal T-tau (A+ T- (N)+) and 42 (33%) abnormal P-tau and T-tau (A+ T+ (N)+). The participants with A+ T+ (N)+ were younger than A+ T- (N)+ at the estimated onset of AD and the initiation of ChEIs. The proportion of 6-month responders to ChEI and deterioration/year after start of treatment did not differ between the AT(N) profiles in any scales. A higher percentage of globally improved/unchanged patients was exhibited in the A+ T- (N)- group after 12, 30 and 36 months of ChEI therapy but not at other assessments. In apolipoprotein E (APOE) ε4-carriers, linear relationships were found between greater cognitive decline/year and higher tau; Mini-Mental State Examination score - T-tau (rs = - 0.257, p = 0.014) and Alzheimer's Disease Assessment Scale-cognitive subscale - P-tau (rs = - 0.242, p = 0.022). A correlation between faster progression in instrumental ADL (IADL) and higher T-tau was also detected (rs = - 0.232, p = 0.028). These associations were not demonstrated in non-ε4-carriers. CONCLUSIONS Younger age and faster global deterioration were observed in AD patients with pathologic tau and neurodegeneration, whereas more rapid cognitive and IADL decline were related to higher P-tau or T-tau in APOE ε4-carriers only. The results might indicate an association between more pronounced tau pathology/neuronal injury and the APOE ε4-allele leading to a worse prognosis. Our findings showed that the AT(N) biomarker profiles have limited utility to predict AD progression rates and, thus, measure change and interpreting outcomes from clinical trials of future therapies.

中文翻译：

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脑脊髓液生物标志物水平：磷酸化的tau（T）和总tau（N）作为阿尔茨海默氏病进展速度的标志物。

背景我们研究了磷酸化tau（P-tau）和总tau（T-tau）的脑脊髓液（CSF）水平与胆碱酯酶抑制剂（ChEI）治疗的短期反应，纵向结局和进展率之间的潜在关联阿尔茨海默氏病（AD）。方法这项前瞻性，观察性研究包括129名临床诊断为轻度至中度AD的参与者，他们接受了腰椎穿刺术。用xMAP技术分析了CSF生物标记淀粉样蛋白-β1-42（Aβ42），P-tau和T-tau。评估了在开始ChEI治疗时以及每三年超过半年的认知，全球，工具和基本活动的日常生活（ADL）能力。结果所有患者均具有异常的Aβ42（A +）。58个人（45％）表现出正常的P-tau和T-tau（A + T-（N）-），12（9％）正常P-tau /正常T-tau（A + T +（N）-），17（13％）正常P-tau /异常T-tau（A + T-（N）+）和42（33 ％）P-tau和T-tau（A + T +（N）+）异常。在估计的AD发作和ChEIs开始时，具有A + T +（N）+的参与者比A + T-（N）+年轻。在任何规模的AT（N）资料之间，对CHEI的6个月缓解者比例和恶化/开始治疗后的年均无差异。在进行ChEI治疗12、30和36个月后，A + T-（N）-组表现出更高比例的总体改善/未改变的患者，但其他评估则没有。在载脂蛋白E（APOE）ε4携带者中，认知下降/年的增加与tau的增加之间存在线性关系。迷你精神状态考试成绩-T-tau（rs =-0.257，p = 0.014）和Alzheimer' ■疾病评估量表认知子量表-P-tau（rs =-0.242，p = 0.022）。还检测到仪器性ADL（IADL）的较快进展与较高的T-tau之间存在相关性（rs =-0.232，p = 0.028）。这些关联在非ε4载体中未得到证实。结论在患有病理性tau和神经退行性变的AD患者中，观察到年龄更年轻，整体恶化更快，而认知和IADL下降更快仅与APOEε4携带者中较高的P-tau或T-tau有关。结果可能表明更明显的tau病理/神经元损伤与APOEε4-等位基因之间的关联导致更差的预后。我们的研究结果表明，AT（N）生物标志物谱在预测AD进展率，因此测量变化和解释未来疗法的临床试验结果方面的作用有限。